Field of the Invention
The present invention relates generally to compositions and methods for the controlled release of an active substance and, in particular, to the use of porous particles having the active substance entrapped therein where the release rate of the substance is modified by the presence of a blocking agent in the pores.
Compositions and methods for the release of an active substance, such as a drug, from a reservoir over time are known, and numerous specific approaches exist to achieve such controlled release. Two widely practiced approaches are of particular interest to the present invention. In the first such approach, a solid core of an active substance is encapsulated in a sustained release coating. The sustained release coating is usually a permeable membrane material which remains intact as the drug diffuses therethrough at a desired rate. Such sustained release coatings are very useful for controlling the release rate of many substances, but are much less useful with soluble and low viscosity substances. Moreover, the release rate is generally not responsive to various environmental conditions, such as pH, ionic strength, and the like.
In the second approach, drugs or other active substances are encapsulated or coated with a material which dissolves or degrades in response to a change in environmental conditions. For example, pH-responsive coatings (referred to as enteric coatings) may be provided on drugs to protect the drug in the low pH environment of the stomach but dissolve when the pH rises as the drug passes to the intestines. Such coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylcellulose phthalate, methylcellulose phthalate, and the like. Although these coatings are very effective in protecting drugs in the stomach, they do not generally provide a controlled release rate once the drug reaches the intestines.
A less widely employed delivery approach utilizes porous polymeric particles for absorbing and releasing drugs and other active substances at a controlled release rate. See, e.g., U.S. Pat. No. 4,692,462, discussed below. In such systems, the diffusion rate of the drug or other active substance through the pores determines the release rate. The diffusion rate, of course, depends on pore size, drug viscosity, temperature, and the like. In the case of drug delivery, drugs absorbed in porous polymeric particles are usually combined in an adhesive or other matrix material as part of a transdermal drug delivery system. In another example, drugs have been adsorbed onto porous resin beads which are then coated with a membrane diffusion barrier, e.g., ethylcellulose, in order to effect sustained release. See, European patent application 171 528, discussed below.
One difficulty with all of these delivery systems has been modifying the system release characteristics in order to achieve a desired release rate for particular active substance. The physical characteristics of drugs and other active substances may vary widely, including changes in viscosity, charge characteristics, molecular weight, and the like, and the release rate in any delivery system may vary widely depending on the nature of the substance which is being delivered. This problem is particularly evident when employing porous particle delivery systems where modification of the pore characteristics can be achieved only within certain limitations.
Thus it would be desirable to provide compositions and methods for the delivery of drugs and other active substances. It would be particularly desirable if the compositions could be readily modified to achieve a desired release rate for active substances having a wide variety of physical and chemical characteristics. It would be further desirable if the compositions could be modified to control the release rate of such divergent active substances under a variety of different external conditions, such as pH, temperature, ionic strength, and the like.